Repair of local bone erosions by combined treatment with parathyroid hormone, osteoprotegerin and anti-tumor necrosis factor in tumor necrosis factor-transgenic mice

Local bone erosions and systemic bone loss are hallmarks of rheumatoid arthritis and cause progressive disability. Tumor necrosis factor (TNF) is a key mediator of arthritis and acts catabolically on bone by stimulating bone resorption and inhibiting bone formation. We hypothesized that the concerted action of parathyroid hormone (PTH), which stimulates bone formation, osteoprotegerin (OPG), which blocks bone resorption, and anti-TNF, which reduces inflammation, could lead to repair of local bone erosions and to inhibition of systemic bone loss. To test this, human TNF-transgenic mice with erosive arthritis and established systemic bone loss were treated with PTH, OPG and anti-TNF. Local bone erosions almost fully regressed, suggesting repair of inflammatory skeletal lesions. In contrast, OPG or anti-TNF alone led to arrest of bone erosions but did not achieve repair. Treatment with PTH alone had no influence on the progression of bone erosions. Local bone erosions showed all signs of new bone formation such as the presence of osteoblasts, osteoid formation and mineralization. Systemic bone loss was completely reversed upon combined treatment, and this effect was mediated by osteoblast stimulation and osteoclast blockade. In contrast to local and systemic bone loss, joint inflammation was only affected by anti-TNF. In summary, we conclude that local and systemic inflammatory bone loss due to TNF can regress, and that repair requires a combined approach by reducing inflammation, blocking bone resorption and stimulating bone formation.